title: Midkine overcomes neurite outgrowth inhibition of chondroitin sulfate proteoglycan without glial activation and promotes functional recovery after spinal cord injury.
abstract: Injuries in the mammalian central nervous system induce a variety of factors which promote or inhibit neuronal axon regeneration/sprouting. However, the inhibitory activities are much stronger, and indeed are the major obstacle to functional recovery. Chondroitin sulfate proteoglycans (CSPGs) are produced by activated glial cells, and are among the strongest inhibitors. Here, we investigated the role of the growth factor midkine (MK), which binds to CSPGs, in neuronal injury. MK expression was induced by spinal cord injury, and was mainly produced by activated astrocytes. A prolonged culture of neurons also produced MK. MK not only enhanced neurite outgrowth on the substratum coated with poly-l-lysine, but also overcame the neurite growth inhibition by the CSPG substratum. Moreover, we found that MK activated neither astrocytes nor microglia as evaluated by morphological changes and cell proliferation or nitric oxide production. These properties would be advantageous for the treatment of neuronal injuries in vivo. Therefore, we next explored the therapeutic effect of MK in a rat spinal cord injury model. MK or vehicle was administered intrathecally for 2 weeks using an osmotic pump after spinal cord contusion injury. Rats treated with MK showed significantly better functional recovery after 5 weeks. These results suggest that MK may offer a potent alternative for the treatment of neuronal injuries without activating glial cells.
authors.affiliation: Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Muramoto
authors.forename: Shiro
authors.initials: S
authors.lastname: Imagama
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Natori
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Wakao
authors.forename: Kei
authors.initials: K
authors.lastname: Ando
authors.forename: Ryoji
authors.initials: R
authors.lastname: Tauchi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hirano
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Shinjo
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D000078792:Midkine; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D016207:Cytokines; D000078792:Midkine
keywords: Chondroitin sulfate proteoglycan; Functional recovery; Midkine; Neurite outgrowth; Spinal cord injury